Endothelin and the tumor microenvironment: a finger in every pie

Abstract

The tumor microenvironment (TME) plays a central role in the development of cancer. Within this complex milieu, the endothelin (ET) system plays a key role by triggering epithelial-to-mesenchymal transition, causing degradation of the extracellular matrix and modulating hypoxia response, cell proliferation, composition, and activation. These multiple effects of the ET system on cancer progression have prompted numerous preclinical studies targeting the ET system with promising results, leading to considerable optimism for subsequent clinical trials. However, these clinical trials have not lived up to the high expectations; in fact, the clinical trials have failed to demonstrate any substantiated benefit of targeting the ET system in cancer patients. This review discusses the major and recent advances of the ET system with respect to TME and comments on past and ongoing clinical trials of the ET system.

Keywords: Cancer; endothelin; epithelial to mesenchymal transition; hypoxia; tumor microenvironment.

Figure 1. The ET system influences the TME the TME in various cancer types.

Within the TME the hypoxia/HIF-1α axis, the β-catenin axis, and its ability to activate immune cells that in turn secrete ET, the ET system is at the center of several autocrine, self-sustaining circuits that promote angiogenesis and EMT. This significant influence of the ET system on cancer progression has prompted numerous preclinical and clinical studies in various cancers such as skin, lung, ovarian and prostate cancer, in which different agents have been used to disrupt the ET system (Created with BioRender.com).

Figure 2. The ET system.

The ETs are derived from prepro ET and are converted into their active form by ECE. ET1 and ET2 bind to the ETAR and the ETBR with equal affinity. However, ET3, the less highly expressed form of ET, has a higher affinity for ETBR. ETAR then causes smooth muscle cell contraction via activation of G-proteins, phospholipase C (PLC) and inositol 1,4,5-triphosphate (IP3) to mediate vasoconstriction. Activation of ETBR causes vasodilation via the release of NO and prostaglandin I2 (PGI2). Under certain conditions, ETBR can mediate vasoconstriction, but not in a clinically relevant manner. Atrasentan and zibotentan are specific inhibitors of ETAR, while BQ788 is a specific antagonist of ETBR. Bosentan and macitentan inhibit both ETAR and ETBR. SPI-1620 is an ETBR agonist (Created with BioRender.com).

Figure 3. The ET system in TME.

(A) ET1 and ET3 increase HIF-1α levels and activate the transcription of angiogenesis genes, leading to increased neovascularization. HIF-1α itself promotes transcription of EDN1, creating a feedback loop that further drives angiogenesis and tumor cell aggressiveness. (B) ET1 up-regulates SNAIL and promotes β-catenin activity to promote EMT. END1 as a transcriptional target of β-catenin, creating a self-sustaining loop. ETAR orchestrates nuclear translocation of the YAP/ZEB1 complex as a co-activator of downstream pro-mesenchymal gene expression of JUN. (C) ET1 can support fibrocyte (FC) and CAF behavior by inducing proliferation, migration, contraction and ECM protein production. ET1 causes increased motility via activation of EGFR signaling mediated by ADAM17, as well as induction of α-SMA, vimentin, and fibronectin. The ET axis mediates cross-talk between fibroblasts, ECs and cancer cells via the p53/YAP/HIF-1α complex, which increases migration and aggressiveness. Binding of ET1 to ETBR promotes EC proliferation, migration and tube formation via up-regulation of MMPs. In addition, ET1 mediates the contraction of ECs via ETBR to control permeability. (D) TAMs express both ET receptors. ET-1 activates TAMs to secrete pro-inflammatory cytokines and ET-1; in addition, macrophages are known to migrate toward ET-1 and promote cancer cell migration, which enables metastasis. DCs express both ET receptors, with ETAR promoting maturation, survival, IL-12 secretion and stimulation of T cells, forming a self-regulatory loop. ETBR mediates DC apoptosis. ET-3 induces DCs to infiltrate the TME and promote tumor growth. ETBR inhibits the endothelial ICAM1 via the release of NO, thus preventing T-cell homing, which promotes immune response and tumor growth (Created with BioRender.com).